A neurodegenerative disease is a disorder caused by the deterioration of certain nerve cells. Changes in these cells cause them to function abnormally, eventually bringing about their death.
Neurodegenerative diseases include familial and sporadic amyotrophic lateral sclerosis (FALS and ALS, respectively), familial and sporadic Parkinson's disease, Huntington's disease, familial and sporadic Alzheimer's disease, olivopontocerebellar atrophy, multiple system atrophy, progressive supranuclear palsy, diffuse lewy body disease, corticodentatonigral degeneration, progressive familial myoclonic epilepsy, strionigral degeneration, torsion dystonia, familial tremor, Gilles de la Tourette syndrome, and Hallervorden-Spatz disease. Most of the diseases are typified by onset during the middle adult years and lead to rapid degeneration of specific subsets of neurons within the neural system, ultimately resulting in premature death. There is no known cure nor is there an effective therapy to slow the progression for any of the stated diseases.
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by progressive muscle weakness during adulthood. Pathological hallmarks are represented by the massive loss of motor neurons together with astrocytosis and microgliosis in the motor cortex, brainstem and spinal cord. Generally, the onset is between the third and sixth decade, typically in the sixth decade. ALS is uniformly fatal, typically within five years. ALS may only be diagnosed when the patient begins to experience asymmetric limb weakness and fatigue, localized fasciculation in the upper limbs and/or spasticity in the legs which typifies onset.
In ALS, the neurons of the cerebral cortex and anterior horns of the spinal cord, together with their homologues in some of the motor nuclei of the brain stem, are affected. The class of neurons affected is highly specific; motor neurons for ocular motility and sphincteric motor neurons of the spinal cord remain unaffected until very late in the disease. Although death occasionally results shortly after the onset of the symptomatic disease, the disease generally ends with respiratory failure secondary to profound generalized and diaphragmatic weakness.
Approximately 10% of ALS cases are family related, the remainder ALS cases being diagnosed as sporadic (90%). The discovery a decade ago by Rosen et al. (1993, Nature, 362, 59-62) of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial cases directed most ALS research to elucidating the mechanism of SOD1-mediated disease. To date, 114 different mutations have been discovered in the SOD1 gene that account for ˜20% of familial ALS cases.
The enzyme superoxide dismutase (SOD), catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. As such, it is an important antioxidant defense in nearly all cells exposed to oxygen. SOD is widely distributed in a living body of animals, plants or microorganisms. More specifically SOD1 is an abundant and ubiquitously expressed protein. Because of its normal function in catalyzing the conversion of superoxide anions to hydrogen peroxide, it was first thought that the toxicity of different SOD1 mutants could result from decreased free-radicals scavenging activity. However, different SOD1 mutants showed a remarkable degree of variation with respect to enzymatic activity. Mice expressing mutants SOD1 G93A (glycine substituted to alanine at position 93) or SOD1 G37R developed motor neuron disease despite elevation in SOD1 activity levels (Cleveland et al., 2001, Nat Rev Neurosc, 2, 806-819). Moreover, SOD1 knockout mice did not develop motor neuron disease (Reaume et al., 1996, Nat Genet, 13, 43-47). Gene disruption for the copper chaperone for SOD1 (CCS) that delivers copper to SOD1 catalytic site had no effect on disease progression in mutant SOD1 transgenic mice (Subramanian et al., 2002, Nat Neurosci, 5, 301-307). Finally, transgenic mice overexpressing a mutant form of SOD1 lacking two of the four histidine residues coordinating the binding of the Cu at the catalytic site still developed motor neurodegeneration despite a marked reduction in SOD1 activity (Wang et al., 2002, Neurobiol Dis, 10, 128-138). Overall, these studies with genetically altered mice indicate that SOD1 mutants cause motor neuron disease through the gain of new toxic properties that is independent of the enzymatic activity involving the copper catalytic site.
The most prevailing view is that the toxicity of SOD1 mutants is related to the propensity of mutant SOD1 to form noxious misfolded protein species and aggregates. Moreover, unlike wild type (WT) SOD1, extracellular mutant SOD1 proteins activate microglia and induce motor neuron death in culture (Urushitani et al., 2006, Nat Neurosci, 9, 108-118), a pathogenic pathway that would be in line with the notion that motor neuron death in mutant SOD1-linked ALS is not strictly cell-autonomous (Boillee et al., 2006, Science, 312, 1389-1392). Interestingly, the oxidation of WT SOD1 is a phenomenon that may promote its aggregation (Furukawa, et al., 2006, PNAS USA, 103, 7148-7153). Considering evidence of oxidative damage in sporadic ALS patients (Ihara et al., 2005, Neurol Res, 27, 105-108) and the abundance of SOD1 protein in cells, it seems plausible that SOD1 molecules might constitute targets of oxidative damage in sporadic ALS.
Since the discovery of genetic mutations in superoxide dismutase 1 (SOD1) in 20% of familial ALS patients and the development of excellent mouse models based on overexpression of ALS-linked SOD1 mutants, many pathogenic pathways to motor neuron death have been elucidated including protein misfolding and aggregation, proteasome impairment, inflammation, reactive oxygen species, excitotoxicity and mitochondrial dysfunction. Based on these hypotheses, multiple approaches for treatment have been tested in the ALS mice including pharmacological approaches and virus-mediated delivery of molecules.
U.S. Pat. No. 5,762,929 reports a pharmaceutical agent that may alleviate symptoms of motor neurons diseases such as amyotrophic lateral sclerosis by oral or parenteral administration. U.S. Pat. No. 5,780,489 reports a method for treating and alleviating the symptoms of amyotrophic lateral sclerosis by administering to a patient an effective amount of a non-cysteine glutathione precursor or a glutathione derivative. U.S. Pat. No. 6,420,429 reports the use of antioxidants for the treatment of diseases such as amyotrophic lateral sclerosis. U.S. Pat. No. 5,843,641; U.S. Pat. No. 5,849,290 and U.S. Pat. No. 6,723,893 report the use of an effective amount of SOD protein or DNA encoding an SOD protein to treat neurodegenerative diseases, specifically amyotrophic lateral sclerosis (ALS). They also report a method of diagnosis of amyotrophic lateral sclerosis using the DNA encoding an SOD protein or a fragment thereof in a PCR reaction.
Although it is well known that SOD1 is a cytosolic protein without specific translocation sequence, there is emerging evidence that both normal and mutant SOD1 can be secreted through secretory pathways (Urushitani, et al., 2006, Nature Neurosci, 9, 108-118). Furthermore, Urushitani, et al. (2006) discovered that extracellular SOD1 mutant can trigger microgliosis and death of motor neurons in culture suggesting a pathogenic mechanism based on toxicity of secreted SOD1 mutant proteins.
There is thus need for new agents, such as monoclonal antibodies which are efficient for the treatment, prevention and/or diagnosis of diseases associated with SOD1 abnormalities.